PROJECT SUMMARY Anorexia nervosa (AN) has the highest mortality rate of any psychiatric disease, and there are no effective treatments. A major obstacle to identifying new therapeutic targets is the lack of insight into causes of the pathophysiological eating behavior. Malnutrition and co-morbid psychiatric illnesses cause dramatic changes in the brain and periphery that complicate efforts to uncover factors responsible for disease onset. The Zeltser lab developed a new mouse model to study AN at the stage of illness prior to disease conversion by taking advantage of an epidemiological observation that is often overlooked ? genetic susceptibility in adolescence. Female mice carrying an allele associated with genetic susceptibility to AN (BDNF-Val66Met) were exposed to social isolation stress and caloric restriction during adolescence. Approximately 40% of these mice exhibit severe self-imposed dietary restriction, sometimes to the point of death. Studies using this mouse model of the pre-AN state identified a novel therapeutic target for AN treatment: arginine vasopressin receptor 1A (AVPR1A). The proposed experiments will map the AVP? AVPR1A circuits in the brain that are necessary and sufficient to suppress feeding and will determine which are potentiated by gene x environment interactions that promote susceptibility to anorexic behavior. Studies outlined in Aim 1 will utilize pharmacological, genetic and pharmacogenetic approaches to define populations of AVPR1A neurons that are necessary and sufficient to suppress feeding in wild-type mice. In parallel, experiments in Aim 2 will use a combination of retrograde tracing and pharmacogenetic techniques to identify neuronal populations that transmit the anorexic AVP signal. Since there are many distinct circuits that regulate feeding, studies in Aim 3 will determine where anorexic effects of AVP and the expression of AVPR1A pathway components are enhanced in hBDNFMet/? females exposed to peri-pubertal social isolation stress. The elucidation of brain circuits that promote anorexic behavior in our mouse model would provide a strong foundation for future efforts to explore whether AVPR1A antagonists that are currently in Phase II clinical trials for other psychiatric indications could benefit some AN patients. Lessons learned will also significantly advance the understanding of how the common BDNF-Val66Met variant exacerbates the effects of social stress on the adolescent brain to increase susceptibility to a variety of anxiety-related and affective disorders.